Dialkyl-sulfoxides and dialkyl-sulfones



United States Patent 3,455,956 DIALKYL-SULFOXIDES AND DIALKYL-SULFONES Hiroshi Hirano, Toyonaka, Katsutada Masuda, Ashiya, Mitsuo Numata, Suita, and Yoshikazu Oka, Amagasaki, Japan, assignors to Takeda Chemical Industries, Ltd., Osaka, Japan No Drawing. Filed Feb. 23, 1966, Ser. No. 529,211 Claims priority, application Japan, Feb. 24, 1965, 40/10,804 Int. Cl. C07d 63/04, 7/04, 65/04 U.S. Cl. 260345.1 2 Claims ABSTRACT OF THE DISCLOSURE Certain dialkyl-sulfones, e.g. Z-tetrahydrofurfuryl-rnethylsulfone and 2-(methyl-sulfonyl-methyl)-tetrahydropyran, have an effective anti-inflammatory activity and are useful in the treatment of inflammatory conditions in patients.

The present invention relates to novel compounds useful as anti-infiammatory agents. More concretely stated, the invention concerns a series of dialkyl-sulfoxides and sulfones.

The inflammatory symptoms in their various manifestations collectively represent one of the serious problems in the clinical field. Though it is known that many diseases are engendered thereby, clinical physicians have often met with difiiculties in removing these symptoms in the therapy of various diseases. To eliminate such harmful symptoms as soon as possible or to prevent the symptoms from occurring is very important for shortening the term of disease and for removing pain as quickly as possible. Many attempts have been made to obtain anti-inflammatory agents suitable for these purposes.

Present anti-inflammatory agents can be divided into two groups: (a) steroidal anti-inflammatory agents, i.e., adrenocortical hormones such as prednisolone, triamcinolone, hydrocortisone, dexamethasone, and the like, and (b) nonsteroidal anti-inflammatory agents which consist mainly of pyrazolidine derivatives such as phenylbutazone, oxyphenbutazone, 1,4-diphenyl-3,S-dioxopyrazolidine, aminopyrine, and the like, and salicylic acid derivatives such as acetyl salicy-clic acid, and the like.

However, those of the former group provoke hypofunction of the anterior pituitary gland and adrenal cortex when they are used for a slightly prolonged period. Once such phenomena occur to a patient, administration of such steroidal anti-inflammatory agents must continue throughout his life. On the other hand, those of the latter group are often accompanied by undesirable side effect on elements of the digestive system such as stomach, intestinal canal, etc. and often disturbe the normal functions of kidney, liver, heart, etc. Therefore, both groups of anti-inflammatory agents necessitate careful administration to patients, especially to those whose illness involves any hormonic and metabolic mechanism and/or functions of their viscera such as stomach, intestinal canal, kidney, liver, heart, etc. Accordingly, debut of an antiinflammatory agent which is safely administrable to patients in a wide field of inflammatory conditions has long been a desideratum in the art.

According to the present invention, novel dialkylsulfones of the formula wherein R is Z-tetrahydrofuryl or 2-tetrahydropyranyl, have an effective anti-inflammatory action.

These novel compounds (I) show an effective antiinfiammatory activity with a lower toxicity than hitherto "ice known anti-inflammatory agents. For example, the median lethal dose (LD of 3,4-dihydro-2-(methyl-sulfonyl methyl)pyran and tetrahydrofurfuryl-methylsulfoxide.

is 1000 mg./kg. and 5001000 mg./kg. of body Weight on intraperitoneal administration in mice, respectively, while the LD of acetyl salicylic acid, phenylbutazone and aminopyrine under the same conditions is 600 mg./ kg., 340 mg./kg. and 300 mg./kg. respectively.

Furthermore, compounds (I) show no such side effects as often accompany steroidal compounds, and show far less side efiects than hitherto-known non-steroidal antiinflammatory agents.

The present compounds (I) also exhibit an analgetic action accompanied by anti-inflammatory action, an inhibitory effect against the lung disease conversion by influenza virus, etc. in addition to the anti-inflammatory action.

It is one object of the present invention to provide such valuable and novel dialkyl-sulfoxides or -sulfones (I) which are useful as anti-inflammatory agents.

Another object of this invention is to provide a method for preparing the novel and useful compounds (I).

A further object is to provide new pharmaceutical compositions containing a compound or compounds (1).

Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

In principle, the present invention relates to new and useful dialkyl-sulfoxides or -sulfones (I).

The fiveor six-membered heterocyclic ring containing one oxygen or sulfur atom as heteroatom, is for example tetrahydrofuran, furan, tetrahydropyran, 3,4-dihydropyran, thiophene, tetrahydrothiophene, etc. The

radical is attached to a car-hon atom, preferably carbon atom adjacent the heteroatom of the ring.

These dialkyl-sulfoxides or -sulfones are prepared by, for example, subjecting the compounds of the formula wherein R is the same as the above. to oxidation.

For the purpose of the oxidation, such conventional oxidizing agents may be employed as, for example, hydrogen peroxide, manganese dioxide, nitric acid, chromic acid, chromic anhydride, lead tetraacetate, organic peracids such as peracetic acid and perbonzoic acid, inorganic per acids or salts thereof such as potassium permanganate, sodium metaperiodate, sodium perchlorate and persulfuric acid, alcohol hydroperoxide' such as tertiary-butyl-hydroperoxide and cumenehydroperoxide, halogen, selenium dioxi-de, ruthenium tetroxide, iodosobenzene, N-bromosuccinimide, dinitrogen pentoxide, etc.

Though the presence of solvents is not essential, particulary when a liquid oxidizing agent is employed, the reaction of this invention is usually carried out in the presence of a suitable solvent, for the purpose of accelerating the reaction or of avoiding side-reactions. The solvent is exemplified as: water, alcohol (e.g. methanol, ethanol), organic acid (e.g. acetic acid, butyric acid, formic acid), halogenated hydrocarbon (e.g. chloroform, carbon tetrachloride, ethylene chloride), hydrocarbon (e.g. benzene, toluene, hexane), ether (e.g. tetrahydrofuran, dioxane), ketone (e.g. acetone, methyl-ethylketone), or the like.

The reaction for preparing the dialkyl-sulfones proceeds desirably under weakly acidic conditions, the preferable pH varying with the objective compound or oxidizing agent employed.

The reaction proceeds under alkaline, neutral or acidic conditions in a solvent, the preferable pH varying with the objective compound or oxidizing agent employed. For example, when hydrogen peroxide or per acids are employed as the oxidizing agents, weakly alkaline conditions are desirable for preparing dialkyl-sulfoxide derivatives and weakly acidic conditions are desirable for preparing dialkyl-sulfone derivatives.

The reaction temperature is suitably selected depending on the objective compounds and the oxidizing agents employed; that is, for preparing dialkyl-sulfoxide, the reaction is usually carried out under cooling and, if desired, at room temperature or at a temperature lower than 60 C., desirably lower than 40 C. On the other hand, for preparing dialkylsulfones, the reaction is usually carried out at room temperature or under heating, and, if necessary, the reaction may be carried out under cooling. In conclusion, dialkyl-sulfoxide may be prepared by employing a mild oxidizing agent or by employing a drastic oxidizing agent under mild condition, while dialkyl-sulfones may be prepared by employing more than Z-equivalent moles of an oxidizing agent and under more drastic conditions than those employed for preparing dialkyl-sulfoxide. A mixture of dialkyl-sulfoxides and sulfones is sometimes obtained by the present process depending upon the reaction conditions, and the mixture is useful as it is for an anti-inflammatory agent, etc.; therefore it is not always necessary to separate the mixture into each component.

The dialkyl-sulfoxides and -sulfones (I) are useful as anti-inflammatory agents and are generally administered in the form of capsule, syrup, oil, injection, ointment, tablet, etc. Pharmaceutical compositions containing one or more of the dialkyl-sulfoxides and -sulfones (I) are prepared according to any conventional means for the preparation of capsules, syrups, oils, injections, etc.

Against such inflammation as is caused by, for example, rheumatic fever, an effective daily dose of the dialkyl-sulfoxides and -sulfones (I) for an adult is usually about 300 mg. to 10 g., desirably 1 to 2 g.

It is to be understood that the following examples of presently preferred embodiments are solely for the purpose of illustration and not to be construed as limitations of this invention, and that many variations may be resorted to without departing from the spirit and scope of this invention. In the examples, g., ml., mg. and mm. are gram, milliliter, milligram and millimeter respectively. Temperatures are all uncorrected, and percentages are all on the weight basis.

Example 1 Tetrahydrofurfuryl-methylsulfide OH H L a-SC s (5.3 g) is added little by little to a solution of sodium periodate (8.6 g.) dissolved in 80 ml. of water with stirring While keeping the reaction temperature not higher than 5 C. with ice. After agitating for one hour, the reaction solution is saturated with sodium chloride. The so-saturated solution is shaken with 200 ml. of chloroform. The chloroform layer is separated and then dried, followed by concentration under reduced pressure to leave an oily residue, from which 3.2 g. of tetrahydrofurfurylmethylsulfoxide is obtained by fractional distillation under reduced pressure as a colorless oily substance boiling at 105108 C./0.3 mm. Hg (Yield: 63%).

Example 2 A chloroform solution (30 ml.) containing 0.0535 g. of perbenzoic acid per ml. is added gradually stirred into a solution of 1.48 g. of tetrahydrofurfuryl-methylsulfide dissolved in 30 ml. of chloroform, under cooling with ice to keep the reaction temperature lower than 5 C.

The reaction solution is agitated for one hour, then 10 ml. of 0.1 normal-sodium thiosulfate is added thereto, followed by vigorous stirring. The chloroform layer is washed with 10% potassium carbonate solution and then with a solution saturated with sodium chloride, followed by drying. The solvent then is distilled off to leave 1.44 g. of tetrahydrofurfuryl-methylsulfoxide as an oily substance, which is confirmed by thin layer chromatography to be the same compound as obtained in Example 1.

*Example 3 6 ml. of a toluene solution containing 0.76 g. of cumene hydroperoxide per ml. is stirred into a solution of 1.48 g. of tetrahydrofurfuryl-methylsulfide dissolved in 20 ml. of chloroform, under cooling with ice. After agitating for one hour, the reaction solution is left for 3 days at room temperature.

After the solvent has been distilled off under reduced pressure, 10 ml. of water is added to the residue and the mixture is shaken with 10 ml. of petroleum ether. The aqueous phase is separated and saturated with sodium chloride and then subjected to extraction twice with 10 ml. each of chloroform. The extracts are combined and dried, followed by distilling off the solvent to leave 1.52. g. of tetrahydrofurfuryl-methylsulfoxide as colorless oily substance.

Example 4 2.9 ml. of 30% aqueous hydrogen peroxide is gradually stirred into a solution of 3.3 g. of tetrahydrofurfurylmethylsulfide dissolved in 40 ml. of acetone, under icecooling. The reaction solution is agitated for 3 hours and then left standing for 5 days at room temperature. The resultant solution is subjected to distillation under reduced pressure to remove acetone. To the residue is added 10 ml. of water, and the mixture is saturated with sodium chloride. So-saturated solution is shaken with 10 ml. of chloroform. The chloroform layer, after drying, is subjected to distillation to give 2.5 g. of tetrahydrofurfurylmethylsulfoxide (Yield: 68%).

Example 5 6 ml. of a toluene solution containing 0.76 g. of cumenehydroperoxide per ml. is added dropwise to a solution of 1.32 g. of tetrahydrofurfuryl-methylsulfide in 20 ml. of methanol. The reaction mixture is warmed at 44-45 C. on a water bath for 4 hours to complete the reaction. The reaction solution is subjected to distillation under reduced pressure. To the residue is added 10 ml. of water and the mixture is shaken with 15 ml. of petroleum ether. The aqueous-phase is saturated with sodium chloride, and then the so-saturated aqueous solution is shaken with 10 ml. of chloroform. After the chloroform layer is dried, it is subjected to distillation to leave 1.48 g. of tetrahydrofurfuryl-methylsulfoxide (Yield: quantitative).

Example 6 Tetrahydrofurfuryl-methylsulfide (1.3 g.) is suspended in water (15 ml.). To the suspension are added 1.8 g. of crystals of N-bromosuccinimide little by little with vigorous stirring to cause reaction with the tetrahydrofurfuryl-methylsulfide, whereby the suspension gradually assumes a state of solution. When the pale-yellow coloration of the solution is no longer eliminated, the total amount of N-bromosuccinimide is found to be about 1.8 g.

The reaction solution is agitated for a further 30 minutes and then it is weakly alkalified by the addition crystalline sodium bicarbonate powder, followed by saturation with sodium chloride. The solution is subjected to extraction with chloroform twice and the chloroform-layers are combined and dried. The combined layer is subjected to distillation to remove the solvent to leave 1.4 g. of tetrahydrofurfuryl-methylsulfoxide as a pale-yellowish oily substance (Yield: This oily substance is confirmed to be the same compound as obtained in Example 1, by thin layer chromatography.

5 Example 7 Furfuryl-methylsulfide CHr-SCH;

(12.8 g.) is stirred dropwise into a solution of sodium metaperiodide (21.4 g.) dissolved in water (200 ml.), under cooling with ice. The solution is agitated for a further 6 hours under cooling with ice, then the precipitating solid is eliminated by the suction filter method. The filtrate is saturated with sodium chloride crystals. The resultant solution is shaken with chloroform and the aqueous layer is subjected to extraction with chloroform three times. The extracts are combined, dried, and then subjected to distillation to remove the solvent to leave an oily substance, from which furfuryl-methylsulfoxide.

(9.5 g.) is obtained by fractional distillation as an oily substance boiling at l00-l02 C./0.l mm. Hg (Yield: 66%).

Example 8 5.0 g. of 30% aqueous hydrogen peroxide is stirred dropwise into 5.8 g. of a solution of Z-(methyl-thiomethyl)-tetrahydropyran dissolved in 30 ml. of acetic acid while keeping the reaction temperature not higher than 30 C. The resultant solution is left standing for 2 hours at room temperature and then an aqueous solution saturated with sodium sulfide is added thereto to reduce excess hydrogen peroxide. The resultant solution is concentrated to dryness under reduced pressure and the residue to extracted with chloroform. The chloroform layer, after drying, is concentrated to give an oily substance, from which 2-(methyl-sulfinyl-methyl)-tetrahydropyran (3.5 g.) is obtained as an oily substance boiling at 105- 106 C./0.7 mm. Hg (Yield: 54%).

Example 9 3,4-dihydro-2-(methyl-thio-methyl)-2H-pyran (2.9 g.) is stirred dropwise into a solution of sodium metaperiodate (4.3 g.) dissolved in Water (40 ml.), under ice-cooling. The resultant solution is agitated for one more hour under ice-cooling to precipitate solid which is eliminated by the suction filter method; the filtrate is then saturated with sodium chloride crystals. The resultant solution is shaken with chloroform. Then the aqueous layer is separated and subjected to extraction with chloroform three times. The chloroform layers are combined and dried, followed by subjecting to evaporation to remove the solvent. The resid ual oily substance is distilled fractionally under reduced pressure to give 3,4-dihydro-2-(methyl-sulfinyl-methyl)- (1.4 g.) as an oily substance boiling at 128132 C./0.4 mm. Hg (Yield: 44%).

Example 10 14.1 ml. of 30% aqueous solution of hydrogen peroxide is stirred dropwise into a solution of tetrahydrofurfuryl-methylsulfide (3.3 g.) dissolved in glacial acetic acid (30 ml.) at about 70 C. The solution is agitated for one more hour at 70 C., the acetic acid is distilled off from the reaction solution under reduced pressure, and

to the residue is added 50 ml. of water. The resultant mixture is alkalified by the addition of sodium carbonate powder and subjected to extraction with chloroform twice. The chloroform layer, after drying, is subjected to distillation to remove the solvent, and to the residual oily substance is added petroleum ether. After cooling, a precipitate is obtained by scrubbing the wall of the reaction vessel. This precipitate is recrystallized from carbon tetrachloride to give 3.4 g. of tetrahydrofurfuryl-methylsulfone as white flakes melting at 37-42 C. (Yield: 83%).

Example 11 10 g. of 30% aqueous solution of hydrogen peroxide is stirred dropwise into a solution of furfuryl-methylsulfide (5.1 g.) dissolved in glacial acetic acid (30 ml.) while the reaction temperature is kept at not higher than 60 C. The reaction mixture is heated at 70 C. for 2 hours, then an aqueous solution saturated with sodium sulfite is added thereto to destroy excess hydrogen peroxide. The resultant solution in concentrated to dryness under reduced pressure, and 50 ml. of water is added to the residue. The mixture is alkalified by the addition of sodium carbonate powder and the resultant solution is subjected to extraction with chloroform twice. The combined chloroform layer, after drying, is subjected to distillation to remove solvent and the residue is recrystallized from a mixture of benzene and petroleum ether to obtain furfurylmethylsulfone t OHr S O2CH3 (4.9 g.) as crystals melting at 65-66 C. (Yield: 77%).

Example 12 10 g. of a 30% aqueous solution of hydrogen peroxide is stirred dropwise into a solution of Z-(methyl-thiomethyD-tetrahydropyran (5.8 g.) in glacial acetic acid (30. ml.) keeping the reaction temperature under 70 C. The reaction mixture is heated at 70 C. for 5 hours, then a saturated aqueous solution of sodium sulfite is added thereto to destroy excess hydrogen peroxide. The resultant solution is concentrated to dryness under re duced pressure. To the residue is added chloroform, and then crystals insoluble in chloroform are filtered off. The filtrate is concentrated to dryness and the residual white crystals are recrystallized from carbon tetrachloride to give 2-(methyl-sulfonyl-methyl)-tetrahydropyran 0/ CHr-SQa-CH;

(6.7 g.) as colorless prisms melting at 103-105 C. (Yield: 94%).

Example 13 3 g. of a 30% aqueous solution of hydrogen peroxide is added to a solution of Z-(methyl-thio-methyl)-thiophone (3 g.) dissolved in glacial acetic acid (3 ml.). The resultant mixture is heated at 70 C. for 14 hours on a water bath. After the reaction mixture is cooled, 1 ml. of Water is added thereto, and the resultant solution is left standing at room temperature to precipitate crystals. After being Washed with Water, the crystals are recrystallized from ethanol to give 2-(methyl-sulfonyl-methyl)-thiophene LSLC r-S O2CH3 (1.7 g.) as colorless needles melting at 94-95 C.

7 8 Having thus disclosed the invention, What is claimed OTHER REFERENCES Gronowitz, C.A. 53:12828 (July 1959). Goldfarb, CA. 54: 9879 (June 1960).

1. 2-tetrahydrofuIifuryl-methylsulfone.

2 (methylsulfonyl methyl) tetrahydmpyran- Katritzky, et a1. C.A. 59; 9468 (October 1963).

5 UNIT sis? SS HENRY R. JILES, Primary Examiner E E C. M. SHURKO, Assistant Examiner 3,288,860 11/1966 Lyness et a1. 260-607 FOREIGN PATENTS 10 Us. 01. X.R.

11,130 8/1962 Japan. 260329, 347.2, 999 

